Typical processes for the manufacture of APM on an industrial scale are: Condensation of N-protected-L-aspartic acid anhydride with L-phenylalanine methyl ester in an organic solvent, followed by removal of the protecting group (U.S. Pat. No. 3,786,039); Direct condensation of a strong-acid addition salt of L-aspartic acid anhydride with L-phenylalanine methyl ester (Jap. Pat. Appln. tokkosho No. 49-14217); and Condensation of N-protected-L-aspartic acid and L-phenylalanine methyl ester in the presence of an enzyme, followed by removal of the protecting group (Jap. Pat. Appln. tokkosho No. 55-135,595).
Industrial production of APM would require a purification step to remove any impurities derived from reactants and by-products, whether the processes described above or any other processes are used. APM may be transferred from the preceeding step to this purification step in the form of a solution, or crude crystals of APM are to be made in solution in this purification step for resin treatment or recrystallization.
The problem was that a large quantity of solvent is required to dissolve APM because it is only slightly soluble in most solvents. For example, its solubility in water at 30.degree. C. is 1 wt %, meaning that 99 Kg water must be used to dissolve 1 Kg of APM; the solubility in pure methanol at room temperature is 1 wt %, and that in pure ethanol is 0.4 wt %.
Solubility increases with increasing temperature; however, since APM undergoes decomposition at elevated temperatures, the highest possible solubility practically attainable is 4 to 5 wt % (at 60.degree. to 70.degree. C.) with the aqueous system.
As a result, a huge volume of APM solution is to be treated and, therefore, very large scale equipments, including piping system, for purification step, as compared with the output of the final product.
Furthermore, APM, if once dissolved, must be isolated from the solution as the final product through crystallization by cooling or other methods. The utility loads required for this process are accordingly very large, providing another disadvantages in commercial operation.
The present inventors' assiduous research to solve these disadvantages associated with conventional processes led them to make the unexpected discovery as described below.
It has been found that the solubility of APM in a mixed solvent of water and a lower alcohol is outstandingly higher than in water or in that lower alcohol alone, if the mixing ratio and temperature are properly selected, and that at low temperatures its solubility in such a mixed solvent is nearly the same as that in water.
In a methanol/water solvent, for example, the solubility of APM, if the mixing ratio and temperature are properly selected, is two to four or more times as large as that in methanol or water alone at the same temperature. What is more surprising is the fact that its solubility in such a mixed solvent is nearly the same as that in water at temperatures lower than 10.degree. C.
The relationship of the solubility of APM in the methanol/water and ethanol/water solvents versus mixing ratio and temperature are illustrated in FIGS. 1 and 2, respectively.
The present inventors have applied these findings to the dissolution (Dissolution herein means not only the dissolving of a solid in a liquid phase, but also the maintaining of the dissolved solid in the solution state.) and crystallization steps in the APM manufacturing process, and succeeded in significantly enhancing productivity per unit space of the entire equipments, or increasing product yields by minimizing thermal decomposition of APM during dissolution.